|
 
 |
| REVIEW ARTICLE |
|
| Year : 2022 | Volume
: 8
| Issue : 1 | Page : 12-19 |
|
Gut dysbiosis: A pathway to glucose dysregulation?
Yakubu Lawal
Department of Internal Medicine, Federal Medical Center, Azare, Nigeria
| Date of Submission | 13-Jun-2021 |
| Date of Decision | 01-Dec-2021 |
| Date of Acceptance | 10-Jan-2022 |
| Date of Web Publication | 8-Jul-2022 |
Correspondence Address:
Yakubu Lawal
Department of Internal Medicine, Federal Medical Center, Azare
Nigeria
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jcrsm.jcrsm_48_21
Various reports have emerged on the possible nature of the complex and dynamic cause-effect relationship between gut dysbiosis and abnormal glucose homeostasis. These reports have suggested or experimented with diverse therapeutic strategies to tackle gut dysbiosis and glucose intolerance caused thereof. This review is aimed at re-aligning reports of pathophysiology and treatment modalities of gut dysbiosis and suggesting focal points of future research that will fast-forward a more encompassing clinical applications in the management of glucose intolerance. Literature search was done using databases including Pubmed, Pubmed Central, Embase, and Google scholar. The search terms used were (“glucose intolerance” OR “glucose dysregulation” OR “diabetes” OR “dysglycemia” OR “prediabetes”) AND (“gut dysbiosis” OR “abnormal gut microbiota” OR “gut microbiota” OR “gut microflora” OR “abnormal gut microflora”). On Initial search, the titles and abstracts of 632 literatures returned were checked for relevance to the review topic. Subsequently, 88 literatures that fulfilled the set criteria were critically reviewed and relevant contents extracted for this review. In conclusion, the treatment of gut dysbiosis can help to ameliorate glucose intolerance. These treatments include prebiotics, probiotics, synbiotics, postbiotics, antibiotics, and even antidiabetics.
Keywords: Diabetes, glucose dysregulation, gut dysbiosis, gut microbiota
How to cite this article:
Lawal Y. Gut dysbiosis: A pathway to glucose dysregulation?. J Curr Res Sci Med 2022;8:12-9 |
| Introduction | |  |
The foundation of the gut microbiota profile is formed after birth following colonization by maternal and environmental microbes, and the building continues for several years.[1] A person's gut micobiota ecosystem is influenced by such factors as maternal age, maternal glycemic status, mode of childbirth, breastfeeding/formula milk practices, diet, rural-urban living style, and xenobiotics (antibiotics, toxins, pathogens, etc.).[1] The variations in composition, diversity, stability, and resilience can lead to harmful or beneficial outcome.
For instance, guts of babies delivered per vaginam or breastfed have been reportedly colonized by Lactobacillus spp, which studies have shown to be anti-diabetogenic; whereas guts of babies delivered via Caesarean section or formula-fed were colonized by common environmental and skin microbes like Staphylococcus, Streptococcus, Propionibacteria, Bacteroides, Clostridium difficile, and Veillonella with potential pathogenicity and diabetogenic properties.[1],[2] Furthermore, Wang et al.[2] demonstrated that neonates of mothers with gestational diabetes mellitus develop gut microbiota profile similar to the mother's. This vertically transmitted gut microbiota profile can serve as a risk factor for the development of diabetes in the offspring in future. More research may be needed to prove this hypothesis.
The gut microbiota in man consists of about 40 trillion microbes. The phyla Firmicutes and Bacteroidetes are the most predominant accounting for 90% of the bacterial phyla. The phylum Firmicutes consists of over 274 genera, namely, Bacillus, Lactobacillus, Mycoplasma, Clostridium while phylum Bacteroidetes comprises about 20 genera, e.g., Bacteroides, which is the most predominant.[3]
Normal gut metabolism relies on the symbiotic associations amongst bacteria, archaea, viruses, fungi, and host immune and neuroendocrine cells. Gut microbiota helps in nutrient breakdown, absorption, and generation of metabolites like amino acids and short-chain fatty acids (SCFAs) essential for glycolysis, the Krebs cycle, etc. It has also been reported that gut microbiota assists in regulating food intake by influencing hormones that affect metabolism and gut-brain axis linked to eating behavior. They also protect against pathogens by inhibiting their growth.[3],[4] It, therefore, can be deduced that abnormal microbiota profile can cause inappropriate energy storage, increased eating behavior, and gut inflammation leading to obesity and glucose intolerance.
The aim of this review is to re-align reports of pathophysiology and treatment modalities of gut dysbiosis and suggest focal points of future research that will fast-forward a more encompassing clinical applications in the management of glucose intolerance.
| Methodology | | |
Literature search was done using databases including Pubmed, Pubmed Central, Embase, and Google scholar. The search terms used were (“glucose intolerance” OR “glucose dysregulation” OR “diabetes” OR “dysglycemia” OR “prediabetes”) AND (“gut dysbiosis” OR “abnormal gut microbiota” OR “gut microbiota” OR “gut microflora” OR “abnormal gut microflora”). On initial search, the titles and abstracts of 632 literatures returned were checked for relevance to the review topic. Studies published over 8 years ago were excluded except for double-blinded randomized controlled clinical trials which were all included. Duplicated literatures were also removed, and subsequently, 88 observational, cohort, experimental studies, and randomized controlled clinical trials were critically reviewed, and relevant contents extracted for this review.
| Evidence of Gut Dysbiosis in People with Glucose Intolerance | | |
Gut dysbiosis is an imbalance of commensal and pathogenic microbiota with the resultant production of harmful microbiota-derived products. These products induce low-grade inflammation contributing to metabolic and degenerative diseases, namely diabetes, obesity, metabolic syndrome and tumorigenesis.[3],[4],[5]
Obese individuals tend to exhibit decreased diversity and an increased Firmicutes/Bacteroidetes ratio in the gut microbiota profile which studies have shown to be diabetogenic.[5] It was also demonstrated that the gut microbiota alone can transmit obese phenotype in humans via varied SCFA production, and impaired energy homeostasis.[5] This results in insulin resistance with eventual development of glucose intolerance.
In a study of African American male veterans, Ciubotaru et al.[6] demonstrated that phylum Bacteroidetes to Firmicutes ratio, Proteobacteria, class Bacteroidia to Clostridia ratio were higher in normal participants than in individuals with prediabetes. However, within the class Clostridia, the abundance of Veillonellaceae and Ruminococcaceae were higher among people with prediabetes. They also reported that high energy and fat diet was associated with decreased Bacteroidaceae/Prevotellaceae ratio as well as decreased Bacteroides/Prevotella ratio.
In a similar vein, Chávez-Carbajal et al.[7] demonstrated that phylum Firmicutes was the most predominant gut microbiota among obese Mexican women with or without metabolic syndrome. They also noted that the gut microbiota in these women carry more genes of lipid metabolic pathways than in non-obese healthy women. In addition, Ahmad et al.[8] reported that Firmicutes, Clostridia, and Negativicutes were predominant while Verrucomicrobia, Bacteroidetes, Proteobacteria, and Elusimicrobia were less abundant among obese Pakistanis with Type 2 Diabetes mellitus (T2DM).
In another report, Nuli et al.[9] demonstrated that gut microbial diversity was higher in people with normal glucose tolerance (NGT) than in T2DM and impaired glucose tolerance. They further reported differential fecal metabolomics associated with different microbiota which are involved in carbohydrate metabolism, biosynthesis of amino acids, etc. Their analysis showed that matricin was positively correlated with Bacteroides and negatively correlated with Actinobacteria, however, more studies are needed to prove the link or causality of the metabolomic to glucose intolerance.
Furthermore, Barengolts et al.[10] demonstrated that gut microbiota biomarkers like lipopolysaccharide-binding protein (LBP), the ratio of LBP to CD14 (LBP/CD14), SCFAs, e.g., propionic, and butyric acid were independent determinants of BMI among African American men after adjusting for age and other risk factors. Therefore, the markers may also be linked to glucose intolerance.
However, conflicting reports had emerged on the benefit or otherwise of some gut microbes in improving glucose metabolism. For instance, some authors demonstrated that Prevotella copri and Akkermansia muciniphila help improve insulin sensitivity and glucose metabolism, while other authors reported otherwise.[11],[12],[13],[14],[15],[16],[17] Cautious and detailed experimental studies are needed before conclusions on causal linkages between specific gut microbial species and glucose intolerance are made. The positive or negative effect of these microbiota may, therefore, depend on other factors, e.g., dietary habits, bowel habits, gut motility, medications, etc.
| Pathophysiology of Dysglycemia Via Gut Dysbiosis | | |
The described pathophysiologic pathways for dysglycemia in gut dysbiosis are interlinked and can all occur in an individual [Figure 1].{Figure 1}
| Dysbiosis-Obesity-Dysglycemia Pathway | | |
Obesity-associated gut microbiota assists in the development of obesity by increasing the efficiency of calorie uptake from food.[18] They ferment indigestible dietary polysaccharides using auto-generated enzymes with resultant SCFA generation.[18] Increased levels of some SCFAs like acetate and conjugated fatty acids are absorbed resulting in increased appetite, increased triglyceride stores, obesity, insulin resistance, and dysglycemia.[18] However, decreased levels of other SCFAs like propionate and butyrate exert obesity effects by decreasing intestinal gluconeogenesis which depresses gut-brain neural circuits with resultant increased appetite, obesity, and gucose intolerance.[19],[20],[21],[22]
Other microbial fermentation products like some bile acids cause obesity via emulsification and absorption of lipids, while other bile acids generated by healthy gut microbiota have been associated with weight reduction, improved insulin, and glucose homeostasis.[23]
| Diet-Dysbiosis-Dysglycemia Pathway | | |
Several authors have demonstrated that obesogenic high fat, low fiber diets caused gut dysbiosis, resulting in metabolic endotoxemia, insulin resistance, and glucose intolerance.[24],[25] This was supported by Shan et al.[26] who demonstrated that high-energy diets with different fat-to-sugar ratios resulted in different gut microbiota profile of similar metagenome/metabolomics and similar dysglycemic states. This means that obesogenic diets irrespective of fat-to-sugar ratio can cause varied forms of gut dysbiosis with similar pro-diabetogenic microbial gene profiles.
| Dysbiosis-Inflammation-Dysglycemia Pathway | | |
Gut dysbiosis may also contribute to glucose intolerance by triggering systemic inflammation.[27] Lipopolysaccharides (LPS) generated from these microbes bind toll-like receptors (TLRs), mainly TLR4, and trigger inflammation. Dietary fat increases intestinal LPS absorption through incorporation into chylomicrons causing metabolic endotoxinemia and systemic inflammation.[27] In addition, Sohail et al.[28] reported that gut dysbiosis alters the balance of gut fermentation, impairs intestinal wall integrity contributing to metabolic endotoxinemia, chronic low-grade inflammation, increased insulin resistance, and impaired glucose regulation.
Furthermore, Parekh et al.[29] reported that gut microflora contributes significantly to the activation and inhibition of autonomic control including the neuroinflammatory inhibitory reflex mediated by the cholinergic nervous system. This may also play a role in chronic low-grade inflammation, insulin resistance, and glucose dysregulation.
| Management of Gut Dysbiosis | | |
Several studies have reported the benefits of various modalities of treating gut dysbiosis including prebiotics, probiotics, synbiotics, postbiotics, antibiotics, antidiabetics, and even bariatric surgery.
| Prebiotics Therapy | | |
Prebiotics has been defined by the Food and Agriculture Organization of the United Nations and the World Health Organization as “non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacterial species already established in the colon, and thus improving the host health.”[30] They include galacto-oligosaccharides, fructo-oligosaccharides, soybean oligosaccharides, inulin, ciclodextrins, gluco-oligosaccharides, xylo-oligosaccharides, lactulose, lactosucrose, isomaltooligosaccharides, etc. They act as nutrients to commensals at the distal end of human gut, thereby maintaining a healthy mix of microbiota with resultant prevention of obesity, insulin resistance, and abnormal glucose metabolism.[31]
Some authors demonstrated that treatment with dietary supplements like the flavonoid-rich Quzhou Fructus Aurantii, inulin-type fructan, Vitamin D, and the Chinese herbal mixture (Huang-Lian-Jie-Du-Decoction) reverses gut dysbiosis shown by the decrease in Firmicutes to Bacteroidetes ratio, increased abundance of the genera Akkermansia and Alistipes.[32],[33],[34],[35],[36],[37],[38] This increased the expression of tight junction proteins, decreased metabolic endotoxinemia, and decreased inflammation, all culminating in the mitigation of insulin resistance/dysglycemia.
In other reports, prebiotics such as oligofructose, chondroitin sulfate, and tryptophan have also been associated with increased plasma glucagon-like peptide-1 (GLP-1) with resultant improved insulin response, reduction in food intake, and improved glucose tolerance. This may occur via growth enhancement of gut bacteria that produce metabolites which simulate GLP-1 secretion.[39],[40]
However, scientists have reported that a person's baseline microbiota can determine response to prebiotics/dietary interventions in preventing or treating glucose intolerance.[41],[42] Therefore, the use of an individual's gut microbiota profile to provide a personalized microbiome-based prebiotic/dietary advice is an area open to further research.
| Probiotics Therapy | | |
A panel of scientific experts defined probiotics as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host.”[43] Probiotics compete to adhere to the gut mucosa, antagonize pathogens, increase mucus production, enhance mucosal integrity, and modulate the immune system. These prevent LPS-induced systemic inflammation, mitigate insulin resistance, and ensure NGT.
Probiotics antagonize pathogens by reducing mucosal pH, preventing their adherence and translocation, and secreting antibacterial defensins, e.g., lactic acid, reducing gut pH, thus inhibiting growth of pathogens.[44],[45],[46],[47] Some of the probiotics e.g., Bifidobacterium infantis, and Lactobacillus acidophilus help to restore mucosal barrier integrity via protein phosphorylation of cytoskeletons and tight junctions.[48],[49],[50] Other probiotics like Lactobacillus brevis, and L. plantarum help to maintain a balanced immune response by exerting control over lymphocytes, macrophages, monocytes dendritic cells, and epithelial cells.[51],[52] All these mechanisms help prevent metabolic endotoxemia, chronic low-grade inflammation, insulin resistance, and glucose intolerance.
Furthermore, a probiotic supplement labeled VSL#3 (a mixture of Lactobacillus acidophilus DSM24735, Lactobacillus delbrueckii, etc) was shown to reduce adiposity, metabolic endotoxinemia, and insulin resistance. These positive effects were due to probiotic action in enriching the number of Bacteriodetes while decreasing the number of obesity-related phyla such as Firmicutes, Proteobacteria, and Tenericutes.[53],[54],[55],[56]
Other antidiabetic actions of probiotics were reported with Lactobacillus casei strain-fermented milk or non-dairy products.[57],[58],[59] The products of fermentation like butyric acid and conjugated linoleic acid (CLA) help to increase insulin sensitivity, GLP-1 secretion, beta-cell function, and thermogenesis with resultant mitigation of obesity, dyslipidemia, and dysglycemia.
A new incretin-based probiotic (Lactobacillus paracasei containing a recombinant microbial delivery vector for long-acting GLP-1 analog) has emerged.[60] This suggests that recombinant incretin-secreting microbes may offer a novel therapeutic strategy for popular treatment of glucose intolerance in the nearest future.
| Postbiotics | | |
The metabolic products of some gut microbiota can be harnessed to reduce obesity, insulin resistance, and blood glucose levels. Some bile acids generated by healthy gut microbiota have been associated with positive effect on glucose and insulin homeostasis.[61],[62]
Conversely, bile acids can regulate gut microbiota through their antimicrobial effects, suggesting that the relationship between microbiota and bile acids is complex and bidirectional and that a dynamic interplay exists between bile acid pool and the bacterial population in the gut.[63],[64] This may be an additional beneficial pathway that can be harnessed commercially to produce synthetic products that can help treat glucose intolerance.
Other postbiotics like butyrate have been linked to enhanced gut wall integrity. Xu et al.[65] have provided evidence that oral butyrate administration reduced local inflammatory cell infiltration, increased gut integrity and intercellular adhesion molecules. This resulted in significantly lowered plasma levels of inflammatory cytokines, and lipopolysaccharide (LPS) resulting in the amelioration of insulin resistance and glucose intolerance.
| Synbiotics | | |
Synbiotic refers to the combination of probiotic(s) and prebiotic(s) as a single medication or supplement.[66] The prebiotic in situ help to improve the survival of beneficial microorganisms (probiotics) added to food and also stimulate the proliferation of specific native gut microbiota.[67] Various reports have shown that the combination of Bifidobacterium or Lactobacillus spp. with fructooligosaccharides resulted in the inhibition of nuclear factor κB and reduced synthesis of tumor necrosis factor α. This, therefore, helps to reduce systemic inflammation, ameliorate insulin resistance, and normalize blood glucose levels.[68],[69],[70]
| Antidiabetics | | |
Some evidence have shown that part of the therapeutic effect of some antidiabetics is via modulation of gut microbiota. Metformin, which is the most extensively used antidiabetic dramatically increased the abundance of A. muciniphila.[21],[71],[70],[71],[72],[73] Other studies reported that antidiabetics including metformin, α-glucosidase inhibitors, GLP-1 agonists 1A, peroxisome proliferator-activated receptors γ agonists, dipeptidyl peptidase-4 inhibitors, and sodium/glucose cotransporter-2 inhibitors, have been shown to help in modulating gut microbiota, thereby contributing to medications' therapeutic action in glycemic control and weight loss. Part of these effects was reported to have occurred via increasing the SCFAs-producing bacteria, responsible for weight loss and suppression of inflammation.[74],[75]
On the one hand, drugs can manipulate gut microbiome composition and metabolic capacity. Conversely, the metabolic activities of the microbiome and its metabolites can also influence pharmacokinetics and pharmacodynamics of antidiabetics.[76] For instance, following acarbose treatment, persons having a gut microbiota enriched with Bacteroides presented more modifications in plasma bile acids as well as better amelioration of their metabolic parameters compared to individuals with gut microbiota dominated by Prevotella.[77] Hence, understanding this bi-directional drug-microbiome interaction and its influence on the clinical outcomes of antidiabetic drugs is an important focal area of future research that can evolve into a better strategy in the selection of antidiabetics to treat diabetes in different individuals.
Other promising modalities of treatment that can modulate gut dysbiosis have been studied and reported. These include fecal microbiota transplantation and bariatric surgery. Zhang et al.[78] appraised the effectiveness of fecal microbiota transplantation in treating gut dysbiosis, obesity, and glucose dysregulation. The results showed improved peripheral insulin sensitivity and lower hemoglobin A1C levels. Several other studies have reported the benefits of fecal microbiota transplantation in treating gut dysbiosis and ameliorating obesity and glucose intolerance.[79],[80],[81]
Furthermore, following different types of bariatric surgeries and duodenal mucosal resurfacing, various studies have reported high gut microbial diversity, gene richness, and a shift from “obese” to a “lean” host phenotype, e.g., dramatic increase in the abundance of A. muciniphila post-surgery or procedure.[82],[83],[84],[85],[86],[87],[88] These result in ameliorating insulin resistance and glucose intolerance.
| Conclusion and Perspectives | | |
Convincing evidences are accumulating on the role of gut dysbiosis in the pathogenesis of glucose intolerance. The foundation for gut dysbiosis can be formed after birth following colonization by abnormal maternal or environmental microbiota or later in life by dietary habits, xenobiotics, infections, obesity, and glucose intolerance.
In general, a higher ratio of phylum Firmicutes to Bacteroidetes, class Clostridia to Bacteroidia, family Prevotellaceae to Bacteroidaceae as well as a higher ratio of genus Prevotella to Bacteroides have been linked to obesity, insulin resistance, and glucose intolerance. However, several studies have shown inconsistencies in the link between some gut microbial species and obesity, insulin resistance, or glucose intolerance. This has been adduced, by several authors, to different factors including different microbial genetic make-up (microbiome) in the same species, different metabolic or fermentation products (metabolome) of the same microbial species, diversity/abundance of other gut microbiota and pathogenic microbes, microbial interaction with ingested medications including antidiabetics, diet, bowel habits, etc.
It can therefore be concluded that the initiation and propagation of glucose intolerance may be related to a cause-effect vicious cycle of gut dysbiosis and hyperglycemia. This means gut dysbiosis may initiate or worsen chronic hyperglycemia and vice versa. It therefore, means that effective treatment of glucose intolerance may involve simultaneous treatment of any degree of hyperglycemia (prediabetes or diabetes), and gut dysbiosis in order to arrest this vicious cycle. However, scientists have reported that a person's baseline microbiota can determine response to prebiotics or probiotics interventions in preventing or treating glucose intolerance. Therefore, the use of an individual's gut microbiota profile to provide a personalized microbiome-based prebiotic/probiotic therapy is an area open to further research.
Postbiotic therapy is also becoming an area of interest in tackling gut dysbiosis with a special focus on the complex and bidirectional relationship between gut microbiota and microbial products. For instance, microbial products or postbiotics like some bile acids have anti-obesity and anti-diabetic properties, and in turn, help to modulate the gut microbiota. This may stand the test of time as a strategy to maintain body weight and glucose homeostasis.
Most anti-diabetics have been reported to, in addition to anti-diabetic action, also treat gut dysbiosis. Conversely, gut microbiota also influences the pharmacokinetics and pharmacodynamics of anti-diabetics. Hence, understanding this bi-directional drug-microbiome interaction and its influence on the clinical outcomes of anti-diabetic drugs is an important focal area of future research that can evolve into a better strategy to individualize treatment of glucose intolerance.
Finally, a new incretin-based probiotic (L. paracasei containing a recombinant microbial delivery vector for long-acting GLP-1 analog) has emerged. This suggests that recombinant incretin-secreting microbes may offer a novel therapeutic strategy to treat gut dysbiosis and glucose intolerance.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Moon Y. Microbiome-linked crosstalk in the gastrointestinal exposome towards host health and disease. Pediatr Gastroenterol Hepatol Nutr 2016;19:221-8.  |
| 2. | Wang J, Zheng J, Shi W, Du N, Xu X, Zhang Y, et al. Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus. Gut 2018;67:1614-25. |
| 3. | de Clercq NC, Groen AK, Romijn JA, Nieuwdorp M. Gut microbiota in obesity and undernutrition. Adv Nutr 2016;7:1080-9. |
| 4. | Belizário JE, Faintuch J, Garay-Malpartida M. Gut microbiome dysbiosis and immunometabolism: New frontiers for treatment of metabolic diseases. Mediators Inflamm 2018;2018:2037838. |
| 5. | Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG. Role of gut microbiota in the aetiology of obesity: Proposed mechanisms and review of the literature. J Obes 2016;2016:7353642. |
| 6. | Ciubotaru I, Green SJ, Kukreja S, Barengolts E. Significant differences in fecal microbiota are associated with various stages of glucose tolerance in African American male veterans. Transl Res 2015;166:401-11. |
| 7. | Chávez-Carbajal A, Nirmalkar K, Pérez-Lizaur A, Hernández-Quiroz F, Ramírez-Del-Alto S, García-Mena J, et al. Gut microbiota and predicted metabolic pathways in a sample of Mexican women affected by obesity and obesity plus metabolic syndrome. Int J Mol Sci 2019;20:438. |
| 8. | Ahmad A, Yang W, Chen G, Shafiq M, Javed S, Ali Zaidi SS, et al. Analysis of gut microbiota of obese individuals with type 2 diabetes and healthy individuals. PLoS One 2019;14:e0226372. |
| 9. | Nuli R, Azhati J, Cai J, Kadeer A, Zhang B, Mohemaiti P. Metagenomics and faecal metabolomics integrative analysis towards the impaired glucose regulation and type 2 diabetes in uyghur-related omics. J Diabetes Res 2019;2019:2893041. |
| 10. | Barengolts E, Green SJ, Chlipala GE, Layden BT, Eisenberg Y, Priyadarshini M, et al. Predictors of obesity among gut microbiota biomarkers in African American men with and without diabetes. Microorganisms 2019;7:320. |
| 11. | De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab 2016;24:151-7. |
| 12. | Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016;535:376-81. |
| 13. | Schneeberger M, Everard A, Gómez-Valadés AG, Matamoros S, Ramírez S, Delzenne NM, et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep 2015;5:16643. |
| 14. | Leal-Díaz AM, Noriega LG, Torre-Villalvazo I, Torres N, Alemán-Escondrillas G, López-Romero P, et al. Aguamiel concentrate from Agave salmiana and its extracted saponins attenuated obesity and hepatic steatosis and increased Akkermansia muciniphila in C57BL6 mice. Sci Rep 2016;6:34242. |
| 15. | Carmody RN, Gerber GK, Luevano JM Jr., Gatti DM, Somes L, Svenson KL, et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 2015;17:72-84. |
| 16. | Anhê FF, Roy D, Pilon G, Dudonné S, Matamoros S, Varin TV, et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut 2015;64:872-83. |
| 17. | Cani PD. Human gut microbiome: Hopes, threats and promises. Gut 2018;67:1716-25. |
| 18. | Harsch IA, Konturek PC. The role of gut microbiota in obesity and type 2 and type 1 diabetes mellitus: New insights into “old” diseases. Med Sci (Basel) 2018;6:32. |
| 19. | De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, Zitoun C, Duchampt A, et al. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014;156:84-96. |
| 20. | Tolhurst G, Heffron H, Lam YS, Parker HE, Habib AM, Diakogiannaki E, et al. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 2012;61:364-71. |
| 21. | Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262-6. |
| 22. | Torres-Fuentes C, Schellekens H, Dinan TG, Cryan JF. The microbiota-gut-brain axis in obesity. Lancet Gastroenterol Hepatol 2017;2:747-56. |
| 23. | Hylemon PB, Zhou H, Pandak WM, Ren S, Gil G, Dent P. Bile acids as regulatory molecules. J Lipid Res 2009;50:1509-20. |
| 24. | Foley KP, Zlitni S, Denou E, Duggan BM, Chan RW, Stearns JC, et al. Long term but not short term exposure to obesity related microbiota promotes host insulin resistance. Nat Commun 2018;9:4681. |
| 25. | Fuke N, Nagata N, Suganuma H, Ota T. Regulation of gut microbiota and metabolic endotoxemia with dietary factors. Nutrients 2019;11:2277. |
| 26. | Shan K, Qu H, Zhou K, Wang L, Zhu C, Chen H, et al. Distinct gut microbiota induced by different fat-to-sugar-ratio high-energy diets share similar pro-obesity genetic and metabolite profiles in prediabetic mice. mSystems 2019;4:e00219-19. |
| 27. | Pindjakova J, Sartini C, Lo Re O, Rappa F, Coupe B, Lelouvier B, et al. Gut dysbiosis and adaptive immune response in diet-induced obesity vs. systemic inflammation. Front Microbiol 2017;8:1157. |
| 28. | Sohail MU, Althani A, Anwar H, Rizzi R, Marei HE. Role of the gastrointestinal tract microbiome in the pathophysiology of diabetes mellitus. J Diabetes Res 2017;2017:9631435. |
| 29. | Parekh PJ, Nayi VR, Johnson DA, Vinik AI. The role of gut microflora and the cholinergic anti-inflammatory neuroendocrine system in diabetes mellitus. Front Endocrinol (Lausanne) 2016;7:55. |
| 30. | Pineiro M, Asp NG, Reid G, Macfarlane S, Morelli L, Brunser O, et al. FAO technical meeting on prebiotics. J Clin Gastroenterol 2008;42 Suppl 3:S156-9. |
| 31. | Younis K, Ahmad S, Jahan K. Health benefits and application of prebiotics in foods. J Food Process Technol 2015;6:1. |
| 32. | Bai YF, Wang SW, Wang XX, Weng YY, Fan XY, Sheng H, et al. The flavonoid-rich Quzhou Fructus Aurantii extract modulates gut microbiota and prevents obesity in high-fat diet-fed mice. Nutr Diabetes 2019;9:30. |
| 33. | Zhang Q, Yu H, Xiao X, Hu L, Xin F, Yu X. Inulin-type fructan improves diabetic phenotype and gut microbiota profiles in rats. PeerJ 2018;6:e4446. |
| 34. | Chen M, Liao Z, Lu B, Wang M, Lin L, Zhang S, et al. Huang-Lian-Jie-Du-decoction ameliorates hyperglycemia and insulin resistant in association with gut microbiota modulation. Front Microbiol 2018;9:2380. |
| 35. | Bakke D, Chatterjee I, Agrawal A, Dai Y, Sun J. Regulation of microbiota by vitamin D receptor: A nuclear weapon in metabolic diseases. Nucl Receptor Res 2018;5:101377. |
| 36. | Ojo B, El-Rassi GD, Payton ME, Perkins-Veazie P, Clarke S, Smith BJ, et al. Mango supplementation modulates gut microbial dysbiosis and short-chain fatty acid production independent of body weight reduction in C57BL/6 mice fed a high-fat diet. J Nutr 2016;146:1483-91. |
| 37. | Song H, Chu Q, Yan F, Yang Y, Han W, Zheng X. Red pitaya betacyanins protects from diet-induced obesity, liver steatosis and insulin resistance in association with modulation of gut microbiota in mice. J Gastroenterol Hepatol 2016;31:1462-9. |
| 38. | Singh DP, Singh J, Boparai RK, Zhu J, Mantri S, Khare P, et al. Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice. Pharmacol Res 2017;123:103-13. |
| 39. | Pichette J, Fynn-Sackey N, Gagnon J. Hydrogen sulfide and sulfate prebiotic stimulates the secretion of GLP-1 and improves glycemia in male mice. Endocrinology 2017;158:3416-25. |
| 40. | Chimerel C, Emery E, Summers DK, Keyser U, Gribble FM, Reimann F. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep 2014;9:1202-8. |
| 41. | Mills S, Lane JA, Smith GJ, Grimaldi KA, Ross RP, Stanton C. Precision nutrition and the microbiome part II: Potential opportunities and pathways to commercialisation. Nutrients 2019;11:1468. |
| 42. | Liu F, Li P, Chen M, Luo Y, Prabhakar M, Zheng H, et al. Fructooligosaccharide (FOS) and galactooligosaccharide (GOS) increase bifidobacterium but reduce butyrate producing bacteria with adverse glycemic metabolism in healthy young population. Sci Rep 2017;7:11789. |
| 43. | Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, et al. Expert consensus document. The international scientific association for probiotics and prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol 2014;11:506-14. |
| 44. | Yang J, Qian K, Wang C, Wu Y. Roles of probiotic lactobacilli inclusion in helping piglets establish healthy intestinal inter-environment for pathogen defence. Probiotics Antimicrob Proteins 2018;10:243-50. |
| 45. | Chen YS, Wang YC, Chow YS, Yanagida F, Liao CC, Chiu CM. Purification and characterization of plantaricin Y, a novel bacteriocin produced by Lactobacillus plantarum 510. Arch Microbiol 2014;196:193-9. |
| 46. | Chikindas ML, Weeks R, Drider D, Chistyakov VA, Dicks LM. Functions and emerging applications of bacteriocins. Curr Opin Biotechnol 2018;49:23-8. |
| 47. | Boirivant M, Strober W. The mechanism of action of probiotics. Curr Opin Gastroenterol 2007;23:679-92. |
| 48. | Urdaci MC, Lefevre M, Lafforgue G, Cartier C, Rodriguez B, Fioramonti J. Antidiarrheal action of Bacillus subtilis CU1 CNCM I-2745 and Lactobacillus plantarum CNCM I-4547 in mice through different cellular pathways. Front Microbiol 2018;9:1537. |
| 49. | Guo S, Gillingham T, Guo Y, Meng D, Zhu W, Walker WA, et al. Secretions of Bifidobacterium infantis and Lactobacillus acidophilus protect intestinal epithelial barrier function. J Pediatr Gastroenterol Nutr 2017;64:404-12. |
| 50. | Putt KK, Pei R, White HM, Bolling BW. Yogurt inhibits intestinal barrier dysfunction in Caco-2 cells by increasing tight junctions. Food Funct 2017;8:406-14. |
| 51. | Kalinina O, Knight KL. Reduction of autoantibody in SLE by probiotic exopolysaccharide-induced inhibitory dendritic cells. Am Assoc Immnol 2018;200:162. |
| 52. | Ueno N, Fujiya M, Segawa S, Nata T, Moriichi K, Tanabe H, et al. Heat-killed body of Lactobacillus brevis SBC8803 ameliorates intestinal injury in a murine model of colitis by enhancing the intestinal barrier function. Inflamm Bowel Dis 2011;17:2235-50. |
| 53. | Pedret A, Valls RM, Calderón-Pérez L, Llauradó E, Companys J, Pla-Pagà L, et al. Effects of daily consumption of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric adiposity biomarkers in abdominally obese subjects: A randomized controlled trial. Int J Obes 2019;43:1863-8. |
| 54. | Minami J, Iwabuchi N, Tanaka M, Yamauchi K, Xiao JZ, Abe F, et al. Effects of Bifidobacterium breve B-3 on body fat reductions in pre-obese adults: A randomized, double-blind, placebo-controlled trial. Biosci Microbiota Food Health 2018;37:67-75. |
| 55. | Kim J, Yun JM, Kim MK, Kwon O, Cho B. Lactobacillus gasseri BNR17 supplementation reduces the visceral fat accumulation and waist circumference in obese adults: A randomized, double-blind, placebo-controlled trial. J Med Food 2018;21:454-61. |
| 56. | Jung S, Lee YJ, Kim M, Kim M, Kwak JH, Lee JW, et al. Supplementation with two probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032, reduced body adiposity and Lp-PLA2 activity in overweight subjects. J Funct Foods 2015;19:744-52. |
| 57. | Naito E, Yoshida Y, Kunihiro S, Makino K, Kasahara K, Kounoshi Y, et al. Effect of Lactobacillus casei strain Shirota-fermented milk on metabolic abnormalities in obese prediabetic Japanese men: A randomised, double-blind, placebo-controlled trial. Biosci Microbiota Food Health 2018;37:9-18. |
| 58. | Cabello-Olmo M, Oneca M, Torre P, Sainz N, Moreno-Aliaga MJ, Guruceaga E, et al. A fermented food product containing lactic acid bacteria protects ZDF rats from the development of type 2 diabetes. Nutrients 2019;11:2530. |
| 59. | Simon MC, Strassburger K, Nowotny B, Kolb H, Nowotny P, Burkart V, et al. Intake of Lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans: A proof of concept. Diabetes Care 2015;38:1827-34. |
| 60. | Ryan PM, Patterson E, Kent RM, Stack H, O'Connor PM, Murphy K, et al. Recombinant incretin-secreting microbe improves metabolic dysfunction in high-fat diet fed rodents. Sci Rep 2017;7:13523. |
| 61. | Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS. Bile acids and the gut microbiome. Curr Opin Gastroenterol 2014;30:332-8. |
| 62. | Trabelsi MS, Lestavel S, Staels B, Collet X. Intestinal bile acid receptors are key regulators of glucose homeostasis. Proc Nutr Soc 2017;76:192-202. |
| 63. | Islam KB, Fukiya S, Hagio M, Fujii N, Ishizuka S, Ooka T, et al. Bile acid is a host factor that regulates the composition of the cecal microbiota in rats. Gastroenterology 2011;141:1773-81. |
| 64. | Zheng X, Huang F, Zhao A, Lei S, Zhang Y, Xie G, et al. Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice. BMC Biol 2017;15:120. |
| 65. | Xu YH, Gao CL, Guo HL, Zhang WQ, Huang W, Tang SS, et al. Sodium butyrate supplementation ameliorates diabetic inflammation in db/db mice. J Endocrinol 2018;238:231-44. |
| 66. | Markowiak P, Śliżewska K. Effects of probiotics, prebiotics, and synbiotics on human health. Nutrients 2017;9:1021. |
| 67. | Gourbeyre P, Denery S, Bodinier M. Probiotics, prebiotics, and synbiotics: Impact on the gut immune system and allergic reactions. J Leukoc Biol 2011;89:685-95. |
| 68. | Olveira G, González-Molero I. An update on probiotics, prebiotics and symbiotics in clinical nutrition. Endocrinol Nutr 2016;63:482-94. |
| 69. | Sáez-Lara MJ, Robles-Sanchez C, Ruiz-Ojeda FJ, Plaza-Diaz J, Gil A. Effects of probiotics and synbiotics on obesity, insulin resistance syndrome, type 2 diabetes and non-alcoholic fatty liver disease: A review of human clinical trails. Int J Mol Sci 2016;17:928. |
| 70. | Eslamparast T, Poustchi H, Zamani F, Sharafkhah M, Malekzadeh R, Hekmatdoost A. Synbiotic supplementation in nonalcoholic fatty liver disease: A randomized, double-blind, placebo-controlled pilot study. Am J Clin Nutr 2014;99:535-42. |
| 71. | Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727-35. |
| 72. | de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care 2017;40:54-62. |
| 73. | Wang ZS, Saha S, Van Horn S, Thomas E, Traini C, Sathe G, et al. Gut microbiome differences between metformin- and liraglutide-treated T2DM subjects. Endocrinol Diab Metab 2017;1:e00009. |
| 74. | Kyriachenko Y, Falalyeyeva T, Korotkyi O, Molochek N, Kobyliak N. Crosstalk between gut microbiota and antidiabetic drug action. World J Diabetes 2019;10:154-68. |
| 75. | Zhang X, Fang Z, Zhang C, Xia H, Jie Z, Han X, et al. Effects of acarbose on the gut microbiota of prediabetic patients: A randomized, double-blind, controlled crossover trial. Diabetes Ther 2017;8:293-307. |
| 76. | Whang A, Nagpal R, Yadav H. Bi-directional drug-microbiome interactions of anti-diabetics. EBioMedicine 2019;39:591-602. |
| 77. | Sayin SI, Wahlström A, Felin J, Jäntti S, Marschall HU, Bamberg K, et al. Gut microbiota regulates bile acid metabolism by reducing the levels of tauro-beta-muricholic acid, a naturally occurring FXR antagonist. Cell Metab 2013;17:225-35. |
| 78. | Zhang Z, Mocanu V, Cai C, Dang J, Slater L, Deehan EC, et al. Impact of fecal microbiota transplantation on obesity and metabolic syndrome – A systematic review. Nutrients 2019;11:2291. |
| 79. | Pérez-Matute P, Íñiguez M, de Toro M, Recio-Fernández E, Oteo JA. Autologous fecal transplantation from a lean state potentiates caloric restriction effects on body weight and adiposity in obese mice. Sci Rep 2020;10:9388. |
| 80. | Leshem A, Horesh N, Elinav E. Fecal microbial transplantation and its potential application in cardiometabolic syndrome. Front Immunol 2019;10:1341. |
| 81. | Zhou Y, Xu H, Huang H, Li Y, Chen H, He J, et al. Are there potential applications of fecal microbiota transplantation beyond intestinal disorders? Biomed Res Int 2019;2019:3469754. |
| 82. | Anhê FF, Varin TV, Schertzer JD, Marette A. The gut microbiota as a mediator of metabolic benefits after bariatric surgery. Can J Diabetes 2017;41:439-47. |
| 83. | Pucci A, Batterham RL. Mechanisms underlying the weight loss effects of RYGB and SG: Similar, yet different. J Endocrinol Invest 2019;42:117-28. |
| 84. | Tremaroli V, Karlsson F, Werling M, Ståhlman M, Kovatcheva-Datchary P, Olbers T, et al. Roux-en-Y gastric bypass and vertical banded gastroplasty induce long-term changes on the human gut microbiome contributing to fat mass regulation. Cell Metab 2015;22:228-38. |
| 85. | Debédat J, Clément K, Aron-Wisnewsky J. Gut microbiota dysbiosis in human obesity: Impact of bariatric surgery. Curr Obes Rep 2019;8:229-42. |
| 86. | Aron-Wisnewsky J, Prifti E, Belda E, Ichou F, Kayser BD, Dao MC, et al. Major microbiota dysbiosis in severe obesity: Fate after bariatric surgery. Gut 2019;68:70-82. |
| 87. | Magouliotis DE, Tasiopoulou VS, Sioka E, Chatedaki C, Zacharoulis D. Impact of bariatric surgery on metabolic and gut microbiota profile: A systematic review and meta-analysis. Obes Surg 2017;27:1345-57. |
| 88. | de Oliveira GH, de Moura DT, Funari MP, McCarty TR, Ribeiro IB, Bernardo WM, et al. Metabolic effects of endoscopic duodenal mucosal resurfacing: A systematic review and meta-analysis. Obes Surg 2021;31:1304-12. |
|
Search Pubmed for